Efficacy and safety of fluticasone furoate/vilanterol or tiotropium in subjects with COPD at cardiovascular risk

Figures & data

Figure 1 Patient disposition.

Abbreviations: FF/VI, fluticasone furoate/vilanterol (100/25 mcg); TIO, tiotropium (18 mcg).

Table 1 Summary of demographic and baseline characteristics

	FF/VI (n=310)	TIO (n=313)
Age, years
Mean (SD)	62.9 (8.1)	62.3 (8.0)
Min–max	42–85	40–86
Sex, n (%), female/male	117/193 (38/62)	104/209 (33/67)
Race and racial combinations, n (%)
White – White/Caucasian/European heritage	302 (97)	305 (97)
African American/African heritage	8 (3)	7 (2)
Asian – East Asian heritage	0	1 (<1)
Body mass index, kg/m^2
Mean (SD)	28.4 (6.0)	28.6 (5.5)
Min–max	16–49	16–62
Smoking history
Current/former smoker, n (%)	161/149 (52/48)	161/152 (51/49)
Pack years, mean (SD)	43.2 (24.5)	45.6 (25.2)
Cardiovascular history or risk factors, n (%)
Hypertension	251 (81)	271 (87)
Hypercholesterolemia	134 (43)	143 (46)
Coronary artery disease	84 (27)	81 (26)
Diabetes	54 (17)	71 (23)
Myocardial infarction	32 (10)	24 (8)
Arrhythmia	16 (5)	27 (9)
Congestive heart failure	14 (5)	15 (5)
Cerebrovascular accident	12 (4)	4 (1)
COPD exacerbation history, n (%)
No exacerbation in past 3 years	145 (47)	136 (43)
≥1 exacerbations in past 3 years	165 (53)	177 (57)
Baseline lung function, mean (SD)
Prebronchodilator FEV1 (L), mean (SD)	1.35 (0.47)	1.35 (0.50)
Prebronchodilator FVC (L), mean (SD)	2.67 (0.78)	2.68 (0.84)
Inspiratory capacity (L), mean (SD)	2.06 (0.60)	2.09 (0.62)
Reversibility, n (%), reversible/non-reversible	101/202 (33/67)	95/213 (31/69)
Postbronchodilator FEV1 (L), mean (SD)	1.46 (0.45)	1.50 (0.46)
Postbronchodilator % predicted normal FEV1, mean (SD)	49.4 (10.5)	49.7 (11.1)
Postbronchodilator FVC (L), mean (SD)	2.90 (0.80)	2.98 (0.85)
Postbronchodilator FEV1/FVC	0.51 (0.10)	0.51 (0.10)
Baseline health outcome scores, mean (SD)
SGRQ-C	48.84 (16.70)	49.70 (18.65)
CAT	18.1 (6.9)	18.6 (7.7)

Abbreviations: CAT, COPD Assessment Test; FEV₁, forced expiratory volume in 1 second; FF/VI, fluticasone furoate/vilanterol (100/25 mcg); FVC, forced vital capacity; SD, standard deviation; SGRQ-C, St George’s Respiratory Questionnaire-COPD; TIO, tiotropium (18 mcg).

Figure 2 Box plot of change from baseline in 24-h weighted mean FEV₁ (L).

Notes: Box represents the IQR, midline represents the median, + represents the mean, whiskers represent 1.5× IQR, circles represent subjects exceeding 1.5× IQR. P=0.201.
Abbreviations: FEV₁, forced expiratory volume in 1 second; FF/VI, fluticasone furoate/vilanterol (100/25 mcg); h, hours; IQR, interquartile range; TIO, tiotropium (18 mcg).

Table 2 Time to onset of action (postdose change from baseline of ≥100 mL) on treatment day 1

Time to onset	Number (%) of subjects
	FF/VI	TIO
n	304	309
5 minutes	110 (36)	72 (23)
15 minutes	37 (12)	66 (21)
30 minutes	25 (8)	38 (12)
60 minutes	23 (8)	30 (10)
120 minutes	23 (8)	32 (10)
240 minutes	21 (7)	16 (5)
Increase of ≥100 mL not met	65 (21)	55 (18)

Abbreviations: FF/VI, fluticasone furoate/vilanterol (100/25 mcg); TIO, tiotropium (18 mcg).

Table 3 Other efficacy endpoints

	FF/VI	TIO	LS mean change difference (95% CI)
Trough (predose) FEV1 (L), n	268	249
Baseline mean (SD)	1.35 (0.47)	1.35 (0.50)
Day 84 mean (SD)	1.43 (0.50)	1.43 (0.51)
LS mean change from baseline (SE)	0.098 (0.013)	0.093 (0.014)	0.005 (−0.029 to 0.039)
Trough (predose) IC (L), n	267	253
Baseline mean (SD)	2.06 (0.60)	2.09 (0.62)
Day 84 mean (SD)	2.13 (0.62)	2.20 (0.65)
LS mean change from baseline (SE)	0.075 (0.022)	0.134 (0.023)	−0.059 (−0.115 to −0.002)
Trough (predose) FVC (L), n	268	249
Baseline mean (SD)	2.67 (0.78)	2.68 (0.84)
Day 84 mean (SD)	2.72 (0.82)	2.80 (0.84)
LS mean change from baseline (SE)	0.050 (0.022)	0.133 (0.023)	−0.083 (−0.138 to −0.028)
Dyspnea symptom score,a n	301	298
Baseline mean (SD)	1.84 (0.86)	1.84 (0.84)
Weeks 1–12 mean (SD)	1.53 (0.76)	1.62 (0.74)
LS mean change from baseline (SE)	−0.35 (0.04)	−0.26 (0.04)	−0.09 (−0.18 to −0.00)
Cough symptom score,b n	299	296
Baseline mean (SD)	1.50 (0.76)	1.56 (0.72)
Weeks 1–12 mean (SD)	1.39 (0.68)	1.44 (0.65)
LS mean change from baseline (SE)	−0.17 (0.03)	−0.15 (0.03)	−0.02 (−0.09 to 0.06)
Sputum production symptom score,b n	297	296
Baseline mean (SD)	1.32 (0.82)	1.35 (0.83)
Weeks 1–12 mean (SD)	1.25 (0.72)	1.26 (0.71)
LS mean change from baseline (SE)	−0.08 (0.03)	−0.10 (0.03)	0.01 (−0.06 to 0.09)
Percent symptom-free periods,c n	297	296
Baseline mean (SD)	2.3 (12.7)	3.0 (14.1)
Weeks 1–12 mean (SD)	5.0 (15.3)	3.8 (13.0)
LS mean change from baseline (SE)	2.9 (0.8)	1.4 (0.8)	1.5 (−0.4 to 3.4)

Notes:

a Scored from 0 (not breathless at rest or upon exertion) to 4 (breathless at rest);

b scored from 0 (none) to 3 (severe);

c 24-h period.

Abbreviations: CI, confidence interval; FEV₁, forced expiratory volume in 1 second; FF/VI, fluticasone furoate/vilanterol (100/25 mcg); FVC, forced vital capacity; h, hours; IC, inspiratory capacity; LS, least squares; SD, standard deviation; SE, standard error; TIO, tiotropium (18 mcg).

Figure 3 Weekly rescue medication use.

Notes: (A) Mean weekly use of albuterol/salmeterol rescue medication in inhalations/day over the 12-week course of the study and (B) mean weekly percentage of rescue-free days over the 12-week course of the study. During Weeks 1–12, the LS mean change difference between groups was (A) −0.37 inhalations (95% CI −0.55 to −0.19) and (B) 9.1% (95% CI 4.0–14.2). Albuterol use was measured as occasions used/day.
Abbreviations: CI, confidence interval; FF/VI, fluticasone furoate/vilanterol (100/25 mcg); LS, least squares; TIO, tiotropium (18 mcg).

Figure 4 Least squares mean change from baseline in (A) total SGRQ-C score and (B) total CAT score at Weeks 4, 8, and 12.

Notes: The LS mean change difference between groups for Week 4 was (A) −2.25 (95% CI −4.00 to −0.51) and (B) −0.9 (95% CI −1.8 to 0.0), for Week 8 was (A) −2.84 (95% CI −4.70 to −0.99) and (B) −0.7 (95% CI −1.6 to 0.2), and for Week 12 was (A) −1.38 (95% CI −3.38 to 0.62) and (B) −0.4 (95% CI −1.3 to 0.5). The MCID of −4 is indicated by a dotted line.
Abbreviations: CAT, COPD Assessment Test; CI, confidence interval; FF/VI, fluticasone furoate/vilanterol (100/25 mcg); LS, least squares; MCID, minimal clinically important difference; SGRQ-C, St George’s Respiratory Questionnaire-COPD; TIO, tiotropium (18 mcg).

Table 4 Adverse eventsa

	FF/VI (n=310)	TIO (n=313)
AEs during treatment, n (%)
Any AE during treatment	113 (36)	99 (32)
Drug-related AE	21 (7)	12 (4)
AE leading to withdrawalb	6 (2)	14 (4)
Serious AEs	10 (3)	10 (3)
Fatal AEs	0	2 (<1)
Most frequentc AEs, n (%)
Headache	18 (6)	23 (7)
Nasopharyngitis	16 (5)	13 (4)
Back pain	9 (3)	9 (3)
Oral candidiasis	9 (3)	5 (2)
AEs of special interest,d n (%)
Cardiovascular effects	13 (4)	15 (5)
Local steroid effects/candidiasis	17 (5)	11 (4)
Hypersensitivity	5 (2)	4 (1)
LRTI excluding pneumonia	3 (<1)	4 (1)
Bone disorders/fractures	3 (<1)	1 (<1)
Pneumonia	3 (<1)	0
Ocular effects/glaucoma	0	1 (<1)

Notes:

a Number of subjects reporting an event (not number of events);

b any AE leading to permanent withdrawal from the study or withdrawal of study drug;

c AEs reported in ≥3% of subjects in either treatment group;

d prespecified AEs of special interest with corticosteroid and LABA treatment.

Abbreviations: AE, adverse event; FF/VI, fluticasone furoate/vilanterol (100/25 mcg); LRTI, lower respiratory tract infection; TIO, tiotropium (18 mcg).